INDIANAPOLIS — It only takes one. One missed block for the Broncos to finally miss all-pro offensive tackle Ryan Clady. One blindside hit by Indianapolis Colts pass rusher Robert Mathis to change the game.

One poorly executed play to send the Broncos to their first loss of the season. And one loss to drop the Broncos to second place behind the undefeated Kansas City Chiefs — the Chiefs! — in the AFC West.

One. When Mathis beat left tackle Chris Clark for a sack and fumble that resulted in a safety in the second quarter Sunday night, the play altered momentum and propelled the Colts past the Broncos 39-33 before an energized sellout crowd of 67,196 fans at Lucas Oil Stadium.

The loss was a Broncos bummer, for so many reasons. Denver fell to 6-1 and saw the end of its franchise-record, 17-game winning streak in regular-season play.

It also spoiled Peyton Manning's emotional return to the city where he played at a Hall of Fame-caliber level for the first 13 seasons of his NFL career.

"I thought they played excellent on defense," Manning said. "Our execution just wasn't as sharp. We couldn't find much of a rhythm. We'll learn from it and be better next time."

In the days leading up the game, Colts owner Jim Irsay undoubtedly spoke too much. Late in the third quarter, perhaps Irsay spoke too soon. It appeared the Broncos were down and out, trailing 33-14 with five minutes left in the quarter.

Showing the type of greatness that should not be easily discarded, and never, ever diminished by a loquacious owner whose team is about to play him, Manning nearly rallied the Broncos to an improbable comeback.

Denver got within 36-30 and had the ball at its 15-yard line with seven minutes left. But on first down, Manning had his arm hit as he threw and his pass was intercepted. Indianapolis soon after kicked a field goal for a 39-30 lead. The Broncos subsequently drove to the Colts' 2-yard line before Ronnie Hillman fumbled on first down, with the Colts recovering with just over three minutes left, all but sealing the victory.

In the days leading up to Manning's highly anticipated return, Irsay implied the quarterback's great passing stats were not conducive to winning Super Bowls. Still, Irsay arranged for a nice pregame tribute that Manning acknowledged by taking off his helmet, waving to the crowd and saying thank you to the fans.

"It was emotional during the tribute," Manning said. "It was a great reception from the fans. It is something I will always remember."

Then the game was about Manning and the quarterback who replaced him, Andrew Luck. And, while Manning played well, throwing three touchdown passes, Luck wound up justifying the Colts' decision to move on.

Luck, whom the Colts drafted with the No. 1 overall pick last year after releasing the injured Manning, threw three touchdown passes and ran for another.

By halftime, the world was reminded why the decision Irsay was confronted with 19 months ago was so difficult. Manning is still very good. Despite the pregame tribute that shook appreciation from Manning's heart that was otherwise steeled for competition, he demonstrated remarkable touch and accuracy on several completions.

He threw a 17-yard scoring pass to Eric Decker to cap his two-play second possession, then executed a nice touch pass to tight end Julius Thomas near the back of the end zone.

Indianapolis' Stanley Havili strips the ball from Broncos returner Trindon Holliday in the first half Sunday. More photos. (John Leyba, The Denver Post)

The Broncos were up 14-10 and Manning had 24 touchdown passes against only two interceptions for the season. Those in the boisterous crowd were pulling hard for the Colts, who improved to 5-2 with the win, but shaking their heads in wonder at what they had seen so many times before.

But the game soon changed, and it was Mathis who made the biggest difference. The Broncos were backed up inside their 10, facing third-and-long with nine minutes left in the second quarter when Manning set to throw. Mathis blindsided him. Lined up at right end, Mathis beat Clark, who had playing well in place of the injured Clady, until he clobbered Manning from behind, whacking the ball away. The ball flew to the far reaches of the end zone for a safety.

The Colts were within 14-12 and after the free kick, Luck had the ball in good field position. An overloaded formation created enough confusion in the Broncos' secondary for Luck to throw a simple pass in the flat to fullback Stanley Havili, who rumbled in for a 20-yard touchdown and a 19-14 lead for the Colts.

Mathis' sack, as it turned out, was essentially a nine-point play.

"It was a speed rush," Clark said about Mathis' play. "He got real deep and just kept running. He's a good player. You just have to be ready and learn from your mistakes."

Manning said: "That was a big play. ... That one was, among others, when we gave them points or field position. And ultimately it was too much to overcome."

Broncos coach John Fox said the Colts' ability to put heat on Manning was a big factor.

"That's a good front," Fox said. "Give them credit. We knew coming in on a fast track, plus a noisy environment, that protection would be a little bit of an issue."

After the Mathis strip, Manning seemed concerned about his protection. The Broncos' offensive line was battered, with right tackle Orlando Franklin joining Clady on the injury list. From the offensive front the Broncos' coaching staff had projected in early June, only left guard Zane Beadles was playing Sunday night at his intended position.

As the teams went into intermission, Luck had outplayed the guy he replaced. Getting the ball at midfield with 1:35 left in the half, Luck went 6-for-6 passing, his last one an 8-yard touchdown strike to tight end Coby Fleener with 10 seconds remaining.

The Colts were up 26-14 at halftime. When Luck scrambled for a 10-yard TD with five minutes left in the third quarter, the Colts had their 33-14 lead.

Manning wasn't going down, though, without making Irsay sweat. He would lead the Broncos to scores on their next three possessions — a short Matt Prater field goal, a gorgeous 31-yard touchdown pass to Demaryius Thomas and a 1-yard touchdown run by Knowshon Moreno.

The Broncos got within reach, but more mistakes on a night full of them doomed a potential comeback for the ages.